Application of KU55933 in preparation of drugs for reversing multidrug resistance of tumor

A multi-drug resistance and drug technology, applied in antineoplastic drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of function loss, poor pharmacokinetics and bioavailability, unsatisfactory effects, etc., and achieve recovery sensitivity sexual effect

Active Publication Date: 2021-06-18
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are two main reasons that limit its clinical application. One is that KU55933 has poor pharmacokinetics and bioavailability due to its high hydrophobicity. The other is that the function of DNA damage repair in various tumor cells is lost, which accelerates gene mutation and further Meet the malignant development of tumors, so KU55933 alone is not effective for those tumor patients with ATM or P53 deficiency

Method used

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  • Application of KU55933 in preparation of drugs for reversing multidrug resistance of tumor
  • Application of KU55933 in preparation of drugs for reversing multidrug resistance of tumor
  • Application of KU55933 in preparation of drugs for reversing multidrug resistance of tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (a) KU55933 can significantly restore the sensitivity of drug-resistant cells to the anticancer drug mitoxantrone

[0039] Harvest parental cells (S1) and ABCG2 high-expression cells (S1-M1-80) and plant them in 96-well plates (8000 cells / well). After 12 hours of complete cell attachment, mitoxantrone (purchased from Shanghai Di Cypress Biotechnology Co., Ltd.) was added to the corresponding wells in a concentration gradient, and the difference in the volume of the drug was filled with phosphate buffered saline (PBS). After 72 hours, 10 μL of 5 mg / ml thiazolium blue (MTT) was added to each well, and incubated at 37 ° C. After 4 hours, suck off the culture medium, add 50 μL of dimethyl sulfoxide (DMSO) to dissolve the crystals after drying, and measure the OD value at 570 nm with a microplate reader; different concentrations (1 μmol / L and 0.3 μmol / L) After the KU55933 (purchased from Shanghai Taosu Biotechnology Co., Ltd.) was combined with gradient concentrations of mit...

Embodiment 2

[0047] (a) KU55933 can significantly restore the sensitivity of drug-resistant cells to the anticancer drug doxorubicin

[0048] Harvest parental cells (S1) and ABCG2 high-expressing cells (S1-M1-80) and plant them in 96-well plates (8000 cells / well). Company) was added into the corresponding wells in concentration gradients, and the difference in the volume of the drug was filled with phosphate buffered saline (PBS). After 72 hours, 10 μL of 5 mg / ml thiazolium blue (MTT) was added to each well, and after incubation at 37 ° C for 4 hours, Aspirate the culture solution, add 50 μL of dimethyl sulfoxide (DMSO) to each well to dissolve the crystals after drying, measure the OD value at 570 nm with a microplate reader; mix different concentrations (1 μmol / L and 0.3 μmol / L) of KU55933 with gradient After the concentration of doxorubicin was combined, the above process was repeated, and a positive control of the combination of 1 μmol / L ABCG2 specific inhibitor FTC and doxorubicin was...

Embodiment 3

[0056] KU55933 can inhibit the drug efflux of ABCG2 and increase the intracellular content of the fluorescent substrate rhodamine 123

[0057]Harvest the parental cells (S1) and ABCG2 high-expressing cells (S1-M1-80) and plant them in 12-well plates (450,000 cells / well). After 12 hours of complete cell attachment, add 1 μmol / L and 0.3 μmol / L The cells were pretreated with KU55933 for 1 hour. At the same time, 1 μmol / L of FTC was used as a positive control. After incubation at 37°C for 2 hours, the culture medium was aspirated, and the cells were washed twice with PBS to wash away the residual drug in the wells. Using a fluorescence microscope, the excitation wavelength is 505nm, and the emission wavelength is 527nm, and the fluorescence intensity of rhodamine 123 in the cells is observed by taking pictures. After observation under a fluorescence microscope, the cells were digested and resuspended in 200 μL PBS for flow cytometry analysis to accurately quantify the content of ...

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Abstract

The invention discloses application of KU55933 in preparation of drugs for reversing multidrug resistance of tumors, and belongs to the technical field of drug application. According to the invention, KU55933 is found to be capable of remarkably reversing tumor multidrug resistance mediated by membrane transporter for the first time, so that ABCG2 high-expression cells recover sensitivity to anti-cancer drugs. The drugs for reversing the multidrug resistance of the tumors can contain KU55933, anti-cancer medicines, carriers and auxiliary agents, can be prepared into a tablet, a particle, a capsule, an oral liquid or an injection form, and can be used for treating and controlling resistant tumors.

Description

technical field [0001] The invention belongs to the technical field of drug application, and in particular relates to the application of KU55933 in the preparation of drugs for reversing tumor multidrug resistance. Background technique [0002] Similar to the phenomenon of bacterial resistance to antibiotics, since the application of chemotherapy drugs in tumor therapy, tumor cells develop resistance to one drug and often lead to resistance to a variety of drugs with different structures and different targets. This phenomenon, which has puzzled tumor biologists for many years, is called tumor multidrug resistance (MDR). About 50 years ago, Goldstein et al. had discovered that HeLa cell lines could develop drug resistance after dactinomycin-induced treatment. Ten years later, June Biedler et al. found that Chinese hamster lungs and fibroblasts resistant to dactinomycin also developed resistance to multiple chemotherapy drugs, such as vinblastine, vincristine and daunorubicin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5377A61K45/06A61K31/136A61K31/704A61P35/00
CPCA61K31/5377A61K45/06A61K31/136A61K31/704A61P35/00A61K2300/00Y02A50/30
Inventor 石智刘坤
Owner JINAN UNIVERSITY
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